Background: Extracorporeal photopheresis (ECP) is effective in immune-mediated disorders. A prospective, uncontrolled pilot study was conducted to evaluate the safety and efficacy of ECP in patients with active Crohn's disease (CD) who were refractory to or intolerant of immunosuppressants and/or anti-TNF therapies. Methods: Patients with moderate-to-severely active CD (Crohn's Disease Activity Index [CDAI] 220-450 points) underwent 12 weeks of ECP treatment (Weeks 1-4: twice weekly, every week; Weeks 5-12: twice weekly, every other week). Clinical response was defined as a decrease in the CDAI of ≥100 points or remission (CDAI <150 points) at Week 12. Patients who responded at Week 12 could receive an additional 12 weeks of ECP treatment (twice weekly, every other week) in an extension study. Results: Twenty-eight patients were enrolled with a mean baseline CDAI score of 314 (range 207-457). At Week 12, 14 patients (50%) responded; 13 patients responded within 6 weeks. Seven patients (25%) attained remission by Week 12. Three of 5 patients with open fistulae at baseline had fistula closure. Response was similar among patients naïve to anti-TNF agents and patients who had previously been refractory or intolerant to anti-TNF agents. Of the 12 patients who entered the extension study, 9 (75%) maintained their response at Week 24. Conclusions: In patients with moderate-to-severely active CD who were refractory to or intolerant of immunosuppressants and/or anti-TNF agents, ECP was well tolerated and induced clinical response (50%) and remission (25%) in patients. Most patients were able to maintain a response with continued treatments. Copyright © 2009 Crohn's & Colitis Foundation of America, Inc.